{"doi":"10.1016/j.ccell.2025.02.008","title":"Restoration of LAT activity improves CAR T cell sensitivity and persistence in response to antigen-low acute lymphoblastic leukemia","abstract":"Chimeric antigen receptor (CAR) T cells induce responses in patients with relapsed/refractory leukemia; however, long-term efficacy is frequently limited by relapse. The inability to target antigen-low cells is an intrinsic vulnerability of second-generation CAR T cells and underlies most relapses following CD22BBz CAR T cell therapy. Here, we interrogate CD22BBz CAR signaling in response to low antigen and find inefficient phosphorylation of the linker for activation of T cells (LAT) limiting downstream signaling. To overcome this, we designed the adjunctive LAT-activating CAR T cell (ALA-CART) platform, pairing a second-generation CAR with a LAT-CAR incorporating the intracellular domain of LAT. ALA-CART cells demonstrate reduced differentiation during manufacturing and increased LAT phosphorylation, MAPK signaling, and AP-1 activity. ALA-CART cells show improved cytotoxicity, proliferation, persistence, and efficacy against antigen-low leukemias that were refractory to clinically active CD22BBz CAR T cells. Restoration of LAT signaling through the ALA-CART platform represents a promising strategy for overcoming multiple mechanisms of CAR T cell failure.","journal":"Cancer Cell","year":2025,"id":511474,"datarank":0.48764512596028625,"base_score":2.8903717578961645,"endowment":2.8903717578961645,"self_citation_contribution":0.4335557636844247,"citation_network_contribution":0.054089362275861516,"self_endowment_contribution":0.4335557636844247,"citer_contribution":0.054089362275861516,"corpus_percentile":null,"corpus_rank":null,"citation_count":17,"citer_count":14,"citers_with_citation_signal":7,"citers_with_endowment":7,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9525,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1224826,"name":"Amanda J Novak","orcid":"0009-0009-8780-7395","position":1,"is_corresponding":false},{"id":310928,"name":"Etienne Danis","orcid":"0000-0002-5651-8111","position":2,"is_corresponding":false},{"id":1370213,"name":"Samantha M. McClellan","orcid":null,"position":3,"is_corresponding":false},{"id":863893,"name":"Lillie Leach","orcid":null,"position":4,"is_corresponding":false},{"id":812479,"name":"Michael Yarnell","orcid":"0000-0002-4557-7255","position":5,"is_corresponding":false},{"id":550588,"name":"Christopher C. Ebmeier","orcid":"0000-0001-7940-6190","position":6,"is_corresponding":false},{"id":273631,"name":"Sarah K. Tasian","orcid":"0000-0003-1327-1662","position":7,"is_corresponding":false},{"id":309020,"name":"M. Eric Kohler","orcid":"0000-0002-1181-0418","position":8,"is_corresponding":false},{"id":1225416,"name":"Catherine Pham‐Danis","orcid":null,"position":0,"is_corresponding":true}],"reference_count":115,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:47:55.918021Z","pmid":"40068599","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}